Angiogenesis is an important physiological process in which new blood vessels form from pre-existing blood vessels. Compounds that target angiogenesis offer a route to treating diseases characterized by poor or abnormal vascularization of biological tissue. Abnormal angiogenesis can trigger pathological conditions such as cancer, chronic inflammation, diabetic retinopathy and arthritis. Insufficient angiogenesis is a major pathological component of chronic wounds or ischemic heart diseases.
Compounds aimed at treating diseases related to angiogenesis typically either inhibit or induce the creation of new blood vessels. Angiogenesis inhibitors are used to prevent new blood vessels from forming in areas where blood vessels should not form. In contrast, angiogenesis promoters are used in areas where the tissue requires new blood vessels to perform essential functions such as repairing wounds. Neo-vascularization should be promoted in such areas in order to transport nutrients to the site.
Angiogenesis can be promoted chemically by various endogenous angiogenic growth factors such as vascular endothelial growth factor (“VEGF”) and fibroblast growth factor (“FGF”). VEGF-A and bFGF have been proposed to increase the blood flow to the damaged area. Cells called “endothelial cells” line mature blood vessels and typically do not proliferate. However, if endothelial cells are activated by an angiogenic growth factor, they will proliferate and migrate into un-vascularized tissue to form new blood vessels.
Blood vessels are surrounded by biological tissue in an extracellular matrix. The formation of new blood vessels is a function of the interactions between endothelial cells and the interaction of the endothelial cells with the extracellular matrix. These interactions are regulated by receptors on the surface of endothelial cells, which are sensitive to particular molecules such as angiogenic growth factors.
Angiogenesis can also be promoted chemically by applying non-endogenous compounds. For example, Eu(III) hydroxide nanorods are reported to have pro-angiogenic properties.
Cerium oxide nanoparticles exhibit interesting physical behavior, which has been exploited for various biological applications. Cerium oxide nanoparticles are typically considered to be antioxidants since they have been shown to scavenge reactive oxygen species or reactive oxygen intermediates. The antioxidant properties of cerium oxide nanoparticles are believed to be a function of the fact that, at the surface of the nanoparticles, cerium can be reversibly oxidized from a +3 state to a naturally stable +4 oxidation state.
Antioxidants typically inhibit, rather than promote, angiogenesis. Accordingly, the conventional wisdom on cerium oxide nanoparticles would suggest that they inhibit angiogenesis. Remarkably, the present inventors have unexpectedly found that cerium oxide nanoparticles also promote angiogenesis and are useful for treating physiological conditions that require the growth of new blood vessels in order to remediate the condition.